CNS recruitment of CD8+ T lymphocytes specific for a peripheral virus infection triggers neuropathogenesis during polymicrobial challenge
| Autor: | Mark T. Curtis, Glenn F. Rall, Kevin J. O'Regan, Christine M. Matullo |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
RNA viruses
Neuroimmunology Brain Edema Pathogenesis CD8-Positive T-Lymphocytes Mice 0302 clinical medicine Cell Movement Viral classification Lymphocytic choriomeningitis virus Cytotoxic T cell Immune Response lcsh:QH301-705.5 Mice Knockout 0303 health sciences T Cells Brain 3. Good health medicine.anatomical_structure Research Article lcsh:Immunologic diseases. Allergy Immune Cells T cell Immunology Central nervous system Immunopathology Lymphocytic Choriomeningitis Biology Lymphocytic choriomeningitis Microbiology Virus 03 medical and health sciences Immune system Antigen Virology Genetics medicine Animals Humans Molecular Biology 030304 developmental biology Multiple sclerosis Immunologic Subspecialties medicine.disease Animal Models of Infection lcsh:Biology (General) Measles virus Co-Infections Parasitology lcsh:RC581-607 030217 neurology & neurosurgery Measles |
| Zdroj: | PLoS Pathogens, Vol 7, Iss 12, p e1002462 (2011) PLoS Pathogens |
| ISSN: | 1553-7374 1553-7366 |
| Popis: | Although viruses have been implicated in central nervous system (CNS) diseases of unknown etiology, including multiple sclerosis and amyotrophic lateral sclerosis, the reproducible identification of viral triggers in such diseases has been largely unsuccessful. Here, we explore the hypothesis that viruses need not replicate in the tissue in which they cause disease; specifically, that a peripheral infection might trigger CNS pathology. To test this idea, we utilized a transgenic mouse model in which we found that immune cells responding to a peripheral infection are recruited to the CNS, where they trigger neurological damage. In this model, mice are infected with both CNS-restricted measles virus (MV) and peripherally restricted lymphocytic choriomeningitis virus (LCMV). While infection with either virus alone resulted in no illness, infection with both viruses caused disease in all mice, with ∼50% dying following seizures. Co-infection resulted in a 12-fold increase in the number of CD8+ T cells in the brain as compared to MV infection alone. Tetramer analysis revealed that a substantial proportion (>35%) of these infiltrating CD8+ lymphocytes were LCMV-specific, despite no detectable LCMV in CNS tissues. Mechanistically, CNS disease was due to edema, induced in a CD8-dependent but perforin-independent manner, and brain herniation, similar to that observed in mice challenged intracerebrally with LCMV. These results indicate that T cell trafficking can be influenced by other ongoing immune challenges, and that CD8+ T cell recruitment to the brain can trigger CNS disease in the apparent absence of cognate antigen. By extrapolation, human CNS diseases of unknown etiology need not be associated with infection with any particular agent; rather, a condition that compromises and activates the blood-brain barrier and adjacent brain parenchyma can render the CNS susceptible to pathogen-independent immune attack. Author Summary There are many CNS diseases, including multiple sclerosis and amyotrophic lateral sclerosis, which have an inflammatory component, though no direct link has been established between incidence and a CNS-resident infectious agent. We reasoned that peripheral immunogens could play a role in CNS disease by inducing an immune response that is “mis-targeted” to the brain. This hypothesis was based on the immunological principle that, while education and activation of naïve cells is an antigen-driven process, recruitment is primarily antigen-independent. We developed a viral co-infection model using measles virus (MV) as a CNS activator and recruiting signal and lymphocytic choriomeningitis (LCMV) as a peripheral immune response initiator. Co-infection with both viruses resulted in significant morbidity and mortality, coincident with LCMV-specific CD8+ T cell trafficking to the brain. Death occurred due to edema, despite an apparent absence of LCMV antigens within the brain, and pathogenesis was CD8+ T cell-dependent, but perforin-independent. Thus, recruitment of peripherally activated CD8+ T cells to the CNS can potentiate neuroinflammation. This work raises the possibility that concomitant immune challenges may be an important cause of the neuroinflammation of some human CNS diseases, perhaps accounting for the inability to identify a discrete pathogenic trigger within affected brain tissues. |
| Databáze: | OpenAIRE |
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